EP1828391A2 - Procede de synthese du (s)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ole - Google Patents

Procede de synthese du (s)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ole

Info

Publication number
EP1828391A2
EP1828391A2 EP05853935A EP05853935A EP1828391A2 EP 1828391 A2 EP1828391 A2 EP 1828391A2 EP 05853935 A EP05853935 A EP 05853935A EP 05853935 A EP05853935 A EP 05853935A EP 1828391 A2 EP1828391 A2 EP 1828391A2
Authority
EP
European Patent Office
Prior art keywords
dehydrogenase
present
formate
glucose
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05853935A
Other languages
German (de)
English (en)
Inventor
Jeffrey C. Moore
Matthew D. Truppo
Jennifer M. Pollard
David J. Pollard
Michael G. Sturr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1828391A2 publication Critical patent/EP1828391A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic

Definitions

  • the present invention relates to processes for the preparation of (S)-I -(3,5- bis(trifluoromethyl)phenyl)ethan-l-ol (CAS # 30071-93-3) which is useful as an intermediate in the preparation of certain therapeutic agents.
  • the present invention provides a process for the preparation of (S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol which is an intermediate in the synthesis of pharmaceutical compounds .
  • the subject invention provides a process for the preparation of (S)-l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-ol via a very simple, short and highly efficient synthesis.
  • novel process of this invention involves the synthesis of (S)-I -(3,5- bis(trifluoromethyl)phenyl)ethan-l-ol.
  • present invention is concerned with novel processes for the preparation of a compound of the formula:
  • This compound is an intermediate in the synthesis of compounds which possess pharmacological activity.
  • such compounds are substance P (neurokinin- 1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
  • the present invention is directed to processes for the preparation of (S)-l-(3,5- bis(trifluoromethyl)phenyl)ethan-l-ol of the formula:
  • the treatment of l-(3,5- bis(trifluoromethyl)-phenyl)ethan-l-one with an alcohol dehydrogenase in the presence of nicotine adenine dinucleotide (NAD) or nicotine adenine dinucleotide phosphate (NADP), and a cofactor recycling system provides (S)-l-(3,5-bis(trifluorornethyl)-phenyl)ethan-l-ol in higher yields, in greater entantiomeric purity and in a more efficient route than the processes disclosed in the art.
  • the treatment of l-(3,5- bis(trifluoromethyl)-phenyl)ethan-l-one with an alcohol dehydrogenase in the presence of nicotine adenine dinucleotide (NAD), and a cofactor recycling system which comprises: a formate source and a formate dehydrogenase; or a glucose source and a glucose dehydrogenase; provides (S)-I -(3,5- bis(trifluoromethyl)-phenyl)ethan-l-ol in higher yields, in greater entantiomeric purity and in a more efficient route than the processes disclosed in the art.
  • the present invention is directed to a process for the preparation of (S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol which comprises the treatment of l-(3,5- bis(trifluoromethyl)-phenyl)ethan-l-one with an alcohol dehydrogenase in the presence of NAD, and a formate source and a formate dehydrogenase to give (S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol.
  • the present invention is directed to a process for the preparation of (S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol which comprises the treatment of l-(3,5- bis(trifiuoromethyl)-phenyl)ethan-l-one with an alcohol dehydrogenase in the presence of NAD, and a glucose source and a glucose dehydrogenase to give (S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol.
  • a specific embodiment of the present invention concerns a process for the preparation of (S)-l-(3,5-bis(trifiuoromethyl)pheny])ethan-l-ol of the formula:
  • Another embodiment of the present invention concerns a process for the preparation of (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol of the formula:
  • the cofactor recycling system includes those which comprise: a formate source and a formate dehydrogenase; or a glucose source and a glucose dehydrogenase.
  • the alcohol dehydrogenase includes those selected from: alcohol dehydrogenase from Rhodococcus erythropolis; alcohol dehydrogenase from Candida parapsilosis; and alcohol dehydrogenase from Candida boidinii.
  • the alcohol dehydrogenase may be present at a concentration of about 3-7 KU/L (Kilo Units/Liter).
  • the alcohol dehydrogenase may be present at a concentration of about 3 KU/L.
  • Kilo Units (KU) are standard units for measuring enzyme activity. These units of standard activity of enzymes are well understood by persons skilled in the art.
  • the formate source includes those selected from sodium formate and formic acid.
  • the formate source may be present at a concentration of about 50OmM.
  • the formate dehydrogenase includes those selected from formate dehydrogenase.
  • the formate dehydrogenase may be present at a concentration of about 2.9-3.8 KU/L (Kilo Units/Liter) (or 0.7-1 g/L).
  • the formate dehydrogenase may be present at a concentration of about 2.9 KU/L (or 0.7g/L).
  • the nicotine adenine dinucleotide may be present at a concentration of about 0.7-1 g/L. In the present invention, the nicotine adenine dinucleotide may be present at a concentration of about 1 g/L.
  • the glucose source includes those selected from glucose.
  • the glucose source may be present at a concentration of about 450-60OmM.
  • the glucose dehydrogenase includes those selected from glucose dehydrogenase 103 (Biocatalytics).
  • the glucose dehydrogenase may be present at a concentration of about 2.1 - 4.2 KU/L (Kilo Units/Liter) (or 0.035-0.7 g/L).
  • the reaction mixture may comprise an aqueous buffer, such as a phosphate buffer.
  • the reaction mixture may further comprise an organic solvent, such as heptane, hexane or pentane.
  • the reaction mixture may further comprise an organic solvent which is heptane.
  • the organic solvent may be present at a concentration of 0-5%v/v.
  • the pH of the reaction mixture is maintained between pH 6-8.
  • the pH of the reaction mixture is maintained between pH 6.5-7.5.
  • the pH of the reaction mixture is maintained between pH 6.8-7.3, such as by the addition of an acid or base.
  • the temperature of the reaction mixture is maintained at about 26-33 deg C. In a further embodiment of the present invention, the temperature of the reaction mixture is maintained at about 30 deg C.
  • the alcohol dehydrogenase, NAD, and a formate source and a formate dehydrogenase may be contacted together in situ, prior to reaction with (S)-I -(3,5- bis(trifiuoromethyl)phenyl)ethan-l-ol.
  • the alcohol dehydrogenase, NAD, and a glucose source and a glucose dehydrogenase may be contacted together in situ, prior to reaction with (S)-I -(3,5-bis(trifiuoromethyl)phenyl)ethan-l-ol.
  • the (S)-l-(3,5-bis(trifluorornethyl)phenyl)ethan-l-ol obtained in accordance with the present invention may be used as starting material in further reactions directly or following purification.
  • the present invention is directed to a process for purification or for enhancing the enantiomeric purity of (S)-l-(3,5-bis(trifluoromethyl)-phenyl)ethan-l-ol which comprises: extracting the reaction mixture with a solvent which comprises heptane; concentrating the solvent; and crystallizing (S)-l-(3,5-bis(trifluoromethyl)-phenyl)ethan-l-ol.
  • extracting the reaction mixture with a solvent which comprises heptane is conducted at a temperature of about 50-55 deg C.
  • the reaction mixture is extracted with a solvent which comprises heptane, and further comprises methanol, ethanol or ethyl acetate.
  • the reaction mixture is extracted with a solvent which comprises heptane and methanol.
  • a solvent which comprises heptane and methanol.
  • the methanol may be present at a concentrtion of about 10% (v/v).
  • the reaction mixture is extracted with a solvent which comprises heptane and ethanol.
  • the ethanol may be present at a concentrtion of about 5- 10% (v/v).
  • the reaction mixture is extracted with a solvent which comprises heptane and ethyl acetate.
  • the ethyl acetate may be present at a concentrtion of about 5-10% (v/v).
  • concentrating the solvent is conducted by vacuum distillation at a temperature of about 40-45 deg C.
  • crystallizing the (S)-l-(3,5-bis(tri- fluoromethyl)phenyl)ethan-l-ol is conducted at a temperature of between about 45 deg C and about -10 deg C.
  • seed crystals of (S)-l-(3,5-bis(tri-fluoromethyl)phenyl)ethan-l-ol are added to the concentrated solvent.
  • seed crystals of (S)-l-(3,5-bis(tri- fluoromethyl)phenyl)ethan-l-ol are present at a concentration of 0.5-l%gram seed/gram of substrate. It will be appreciated by those skilled in the art that this alternate embodiment may be repeated in an itterative manner to further enhance the enantiomeric purity of (S)-l-(3,5- bis(trifluoromethyl)-phenyl)ethan-l-ol with each subsequent cycle.
  • Another aspect of this invention is directed to (S)-l-(3,5-bis(trifluoro- methyl)phenyl)ethan-l-ol which is present in an enantiomeric purity (enantiomeric excess) of greater than 90%, greater than 95%, greater than 98%, greater than 99%, greater than 99.5% (enantiomeric excess) or greater than 99.9% (enantiomeric excess).
  • Formate dehydrogenase The en2yme reaction used 5OmM phosphate buffer pH 7.0. Sodium formate (50OmM) and NAD (lg/L) were dissolved in the buffer followed by the addition of the enzymes (RE alcohol dehydrogenase (3KU/L) and formate dehydrogenase (0.7g/L or 2.88 KU/L)). l-(3,5- Bis(trifluoromethyl)phenyl)ethan-l-one (CAS 30071-93-3) was added to the reaction as a single solution (100g/L). pH was controlled at pH 7.0 using 2N sulphuric acid. Reaction was run for 28 to 40 hours at 30 deg C. Conversion > 95% was usually achieved by 40 hours with enantiomeric excess >99%.
  • the product was isolated by two 1 A volume extractions in heptane at 50 deg C, followed by V ⁇ volume water wash and vacuum concentration by distillation (2-3 fold volume concentration at 40 deg C). For crystallization the solution was cooled from 45 deg C to 35 deg C (200g/L alcohol concentration in heptane). Seeding with (S)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol at 1% g/gram of substrate was completed at 35 deg C, followed by 1 hour of aging and cool down to -10 deg C. The crystallization procedure rejects impurities such as residual ketone. Final material purity >99% was produced with Enantiomeric excess > 99%.
  • the enzyme reaction used 5OmM phosphate buffer pH 7.0. Sodium formate (50OmM) and NAD (0.7- lg/L) were dissolved in the buffer followed by the addition of the enzymes (RE alcohol dehydrogenase (3-7 KU/L), formate dehydrogenase (0.7-1 g/L or 2.9-3.74 KU/L)) and heptane (0- 5%v/v). l-(3,5-Bis(trifluoromethyl)phenyl)ethan-l-one was added to the reaction as a single solution (10-110g/L). pH was controlled between pH 6.8-7.3 using 2N sulphuric acid. Reaction was run for 28 to 40 hours at 26-33 deg C.
  • the process may be performed by replacing the alcohol dehydrogenase (ADH) from Rhodococcus erythropolis with the ADH from Candida parapsilosis or ADH from Candida boidinii.
  • ADH alcohol dehydrogenase
  • the enzyme reaction uses 5OmM phosphate buffer pH 7.0. Glucose (450-60OmM) and NAD (0.7- lg/L) were dissolved in the buffer followed by the addition of the enzymes (RE alcohol dehydrogenase (3-7 KU/L), glucose dehydrogenase 103 (Biocatalytics) (0.035-0.7 g/L or 2.1- 4.2 KU/L)) and heptane (0-5%v/v). l-(3,5-Bis(trifluoromethyl)-phenyl)ethan-l-one was added to the reaction as a single solution (10-1 lOg/L). pH was controlled between pH 6.8-7.3 using 2N sulphuric acid. Reaction was run for 20-30 hours at 26-33 deg C. Conversion > 95% was achieved by 20 hours with enantiomeric excess >99%.
  • the product was isolated by three 1/2 volume extractions in heptane with ethanol 15% or methanol 10% or 5-10% ethyl acetate at 25 deg C, followed by Vi - 1 water wash and vacuum concentration by distillation(40-55 deg C) with a 2-3 fold concentration.
  • the solution was cooled from 45 deg C to 35 deg C (80g/L - 200g/L alcohol concentration in heptane). Seeding with (S)-l-(3,5-bis(trifluoromethyl)phenyl)-ethan-l-ol at 0.5 - 1% g/gram of substrate was completed at 35 deg C, followed by 1 hour of aging and cool down to -10 deg C.
  • the crystallization procedure rejects impurities such as residual ketone (upto 20% ketone rejection).
  • Theroduct was dried at room temperature and full vacuum. Final material purity >99% was produced with EE > 99%.
  • the route to (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol is shown above. Recycling of the required NADPH cofactor is completed using glucose dehydrogenase with glucose.
  • the enzyme reaction uses 20OmM phosphate buffer (pH 7) with 50OmM glucose and NADP at l-2g/L.
  • the oxidoreductase is KRED 101 from Biocatalytics Inc at 10-20kU/L.
  • Glucose dehydrogenase is used to recycle the cofactor.
  • Ketone is added to the reaction as a solution and pH controlled at pH 7 by 2N sulphuric acid. Reaction time is around 30-40 hours at 30 deg C with enantiomeric excess of >99%.
  • the (R)-l-(3,5-bis(trifluoromethyl)phenyl)ethan-l-ol is isolated by any of the procedures described for the (S) alcohol routes above.
  • reaction conditions other than the particular conditions as set forth herein above may be applicable as a consequence of variations in the reagents or methodology to prepare the compounds from the processes of the invention indicated above.
  • specific reactivity of starting materials may vary according to and depending upon the particular substituents present or the conditions of manufacture, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
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  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne de nouveaux procédés pour préparer du (S)-1-(3,5-bis(trifluorométhyl)phényl)éthan-1-ole (CAS # 30071-93-3). Ce composé sert d'intermédiaire dans la synthèse de composés développant une activité pharmacologique.
EP05853935A 2004-12-16 2005-12-12 Procede de synthese du (s)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ole Withdrawn EP1828391A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US63673504P 2004-12-16 2004-12-16
PCT/US2005/045125 WO2006065840A2 (fr) 2004-12-16 2005-12-12 Procede de synthese du (s)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ole

Publications (1)

Publication Number Publication Date
EP1828391A2 true EP1828391A2 (fr) 2007-09-05

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Application Number Title Priority Date Filing Date
EP05853935A Withdrawn EP1828391A2 (fr) 2004-12-16 2005-12-12 Procede de synthese du (s)-1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-ole

Country Status (7)

Country Link
US (1) US20080090274A1 (fr)
EP (1) EP1828391A2 (fr)
JP (1) JP2008523808A (fr)
CN (1) CN101080494A (fr)
AU (1) AU2005317189A1 (fr)
CA (1) CA2590947A1 (fr)
WO (1) WO2006065840A2 (fr)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6468781B1 (en) * 1999-07-08 2002-10-22 Bristol-Myers Squibb Company Stereoselective reductive amination of ketones
WO2002033110A2 (fr) * 2000-10-17 2002-04-25 Pcbu Services, Inc. PRODUCTION D'ACIDES α-HYDROXY-CARBOXYLIQUES A L'AIDE D'UN SYSTEME D'ENZYME COUPLE
DE10112401A1 (de) * 2001-03-13 2002-09-19 Degussa Alkohol-Dehydrogenase und deren Verwendung
US6764842B2 (en) * 2001-03-28 2004-07-20 Merck & Co., Inc. Enantioselective bioreduction for the preparation of integrin receptor antagonist intermediates
FR2826650A1 (fr) * 2001-07-02 2003-01-03 Rhodia Chimie Sa Procede de reduction enantioselectif d'une cetone aromatique prochirale comprenant au moins un groupe trifluoromethyle sur le cycle aromatique
US7109004B2 (en) * 2002-07-10 2006-09-19 Merck & Co., Inc. Process for reducing an alpha-keto ester

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006065840A2 *

Also Published As

Publication number Publication date
CN101080494A (zh) 2007-11-28
WO2006065840A2 (fr) 2006-06-22
JP2008523808A (ja) 2008-07-10
AU2005317189A1 (en) 2006-06-22
CA2590947A1 (fr) 2006-06-22
WO2006065840A3 (fr) 2006-08-24
US20080090274A1 (en) 2008-04-17

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